Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions

The canonical AD pathological cascade posits that the accumulation of amyloid beta (Aβ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a sample of over 1300 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and APOE-ε4 homozygotes are more susceptible to the effects of Aβ on the primary accumulation of tau, with greater EC tau for a given level of Aβ. Furthermore, we observed for individuals who have rare risk variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and/or APOE-ε4 homozygotes there was a greater spread of primary tau from the EC into the neocortex. These findings offer insights into the function of sex, APOE and microglia in AD progression, and have implications for determining personalised treatment with drugs targeting Aβ and tau.


Introduction:
For more than a century there were no disease modifying treatments for AD.The recent successful trials of Lecanemab and Donanemab have shown that reducing cortical amyloidbeta plaques (Ab) led to significant slowing of cognitive decline; however, our grasp on the precise scope and conditions under which anti-amyloid immunotherapy delivers benefits remains unclear 1,2 .These monoclonal antibodies have been designed based on the amyloid hypothesis, wherein AD follows a canonical cascade, with the accumulation of Ab being the primary event accelerating tau accumulation and spread from the entorhinal cortex (EC) into the neocortex leading to cognitive decline 3 .Substantial evidence supports the role of pathological Ab aggregates as a primary event in both sporadic and genetically dominant forms of AD 4 .In particular, individuals with dominantly inherited AD mutations show a predictable and sequential evolution of AD pathophysiology with Ab accumulation leading to tau accumulation and subsequent spread 5 .However, these genetically dominant forms of AD are rare and the evolution of sporadic late-onset AD is influenced by a multitude of genetic and lifestyle factors, with the relative penetrance of the canonical AD cascade profoundly affected by genetic variation and comorbidities 6,7 .This is particularly pertinent as both Lecanemeb and Donenamab had varying treatment effects based on the primary outcome in females, and, both Lecanemab and Donanemab showing no significant effects of treatment on the primary outcome in homozygotes for the APOE-ε4 allele 1 2 .Therefore, it is critical to quantify the impact genetic variation has on the cascading effects of Ab on entorhinal tau accumulation and subsequent spread into the neocortex to best understand who to treat with these drugs.
The ε4 allele of APOE is the strongest risk factor for clinical sporadic late-onset AD, conferring an increased risk (i.e.odds ratio OR) of AD compared to APOE-ε3 homozygotes of up to 3.46 OR for ε4 heterozygotes and 13.04 OR for APOE-ε4 homozygotes 8 , with APOE-ε4 homozygosity having a near complete penetrance for Ab positivity 9 .Interestingly, the APOE-ε4 allele also has a marked increase in the risk of developing AD in Ab positive individuals, suggesting additional effects beyond Ab 10 .Multiple lines of evidence link the APOE4 isoform to reduced homeostatic clearing of Ab 6,[11][12][13] .This aberrant function of APOE4 occurs through dysfunction in multiple cell types in the brain that play diverse roles in AD pathogenesis, including neurons, microglia, and astrocytes 11,14 .Regarding Ab, APOE4 increases the accumulation of cortical Ab by reducing the dissolution of soluble Ab 15 and impairs the clearance of Ab by disrupting the blood brain barrier 14 .Further, APOE4 has been implicated in increased tau accumulation, with increased levels of APOE4 resulting in increased tau phosphorylation and interneuronal spread of tau 11,14,16,17 .Therefore, APOE is not only involved in amyloidosis but also in downstream and parallel events such as the development of tau pathology.
Alongside the APOE-ε4 allele, rare genetic polymorphisms in TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) have also been shown to be significant risk factors for sporadic late-onset AD 18 .TREM2 is a transmembrane protein expressed in microglia and performs critical functions in the immune response to AD pathology.TREM2 is involved in signalling cascades as well as the transition of microglia to a disease activated state, with a lack of functional TREM2 profoundly impacting microglia function [19][20][21] .Multiple TREM2 polymorphisms have been linked to an increased risk of AD, of which R47H is the most widely studied 18 .Previous work investigating this variant in animal models shows that rare polymorphisms lead to a hypofunctional form of TREM2 promoting tau seeding and spreading 22 .Multiple other genetic variants on the TREM2 gene have been linked to increased risk of AD and negatively affect the function of TREM2 in-vitro 18,20,21,23,24 .These variants may have an additive loss of function or alternatively may be in linkage disequilibrium with the same functional variant 25 .How trait variation in TREM2 impacts different phases of the AD pathological cascade is yet to be fully elucidated in humans and offers an approach to study how dysfunctional TREM2 impacts microglial functions leading to increased burden of Ab and tau.
Sex plays an important role in the pathogenesis of AD, with dementia incidence higher in females in late life 26 .Furthermore, females have consistently been shown to have higher tau tangle load at autopsy then men [27][28][29] .This post mortem work is well supported in-vivo with multimodal neuroimaging studies showing females are susceptible to higher levels and faster accumulation rates of tau for a given level of Ab than their male counterparts [30][31][32][33] .Whether these increases are specific to Ab influences on primary accumulation of tau in the EC, or tau spreading mechanisms from the EC into the neocortex is not well resolved.Furthermore, it is not clear if this finding in females is due to, or, exacerbated by varied immune responses such as TREM2-related microglial dysfunction.
Here, we use causal path modelling to assess how genetic variation impacts the AD pathological cascade (Figure 1).Using data from within subject multimodal PET and whole genome sequencing (WGS) in a sample of 1354 individuals we probe different stages of the AD cascade to understand how genetic variation in sex, APOE-ε4 and TREM2 exacerbate AD pathology.We tested the effect of genetic variation through pathways mediated by Ab or via non-Ab pathways, that is, primary tau accumulation in the EC and spread into the neocortex after accounting for Ab.Our causal path is structured assuming that there are stages in the AD cascade, with the initial event being Ab deposition, followed by Ab-related deposition of tau in the EC, followed by tau spreading from the EC into the neocortex (Figure 1).

Participants
We pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study as a discovery sample (n=628, 79% cognitively normal) and drew a racially diverse replication sample (n=726, 76% cognitively normal) from the Health and Aging Brain Study-Health Disparities (HABS-HD) cohort.Participants had varying levels of Aβ, EC tau and neocortical tau as defined using the meta temporal (MetaTemp) ROI 34 .Furthermore, we extracted genetic information from participants assessing the number of APOE-ε4 alleles in both samples, as well as a binary indicator for TREM2 risk variant carrier status in the discovery sample.Due to the limited TREM2 SNPs data in the HABS-HD, we omitted this variable from our replication analysis (Table 1).

:
Causal effects of different genotypes on Aβ.

Causal effects of different genotypes on EC-tau.
Next, we built a causal path model (Figure 2) to test the main and interactive effects of different genotypes on EC tau (Methods EQ1).Within the discovery sample, we observed significant main effects of Aβ (β=0.0013,P<0.0001) and age (β=0.003,P=0.0072) on EC tau.Furthermore, we observed significant interactions between Aβ and APOE-ε4(2-alleles) (β=0.002,P=0.002), and Aβ and sex(F) (β=0.0008,p=0.032).These interactions indicate that, for a given level of Aβ, APOE-ε4 homozygotes and females had significantly more tau in the EC (Figure 2.).In addition, we observed a significant interaction between TREM2 and sex, whereby female TREM2 risk variant carriers had the greatest levels of EC tau (β=0.124p=0.0407) (Supplementary Table 4).Visualising the marginal effects highlights these results showing that APOE-ε4 homozygotes and females have greater EC tau, and these differences increase with Aβ load (Figure 2).We observed highly similar interaction terms in the HABS-HD sample, observing Aβ interacts with APOE-ε4(2-alleles) (β=0.0037,P=0.018) and sex(F) (β=0.0013,p=0.032) (Supplementary Table 5).These interactions replicate results showing that for a given level of Aβ, APOE-ε4 homozygotes and females have significantly more tau in the EC (Figure 2.).Our results are likely not confounded by race in the replication sample, as when self-reported race was included as a main effect and interaction term with genetic variables in our model, none of these added variables had a significant influence on EC tau (Supplementary Table 6).

Causal effects of different genotypes on MetaTemp tau.
We then built a causal path model (Figure 3) to test the main and interactive effects of different genotypes on MetaTemp tau (Methods EQ2).To allow for an accurate estimation of the causal effects when two continuous variables interact, we segmented Aβ into four bins (<10CL, 10-40CL, 40-60CL and >60CL) when including it as an interactive term with EC tau.This Aβ variable is then used as a candidate variable when selecting interaction terms for the causal path model for MetaTemp tau.Continuous Aβ is still included as a main effect variable in model selection.Within the discovery sample, we observed significant main effects of EC tau (β=0.364,P<0.001), TREM2 risk variant carrier status (β=-0.3580p=0.0001) and APOE-ε4 homozygosity (β=-0.3580p=0.0001) on MetaTemp tau.In addition, we observed significant interactions between EC tau and high Aβ (>60CL) (β=0.019p=0.049),EC tau and APOE-ε4(2alleles) (β=0.364,P<0.001), and EC tau and TREM2(1) (β=0.309,P<0.001).Individuals with high levels of Aβ, APOE-ε4 homozygotes and individuals with a TREM2 risk variant carrier status having greater downstream MetaTemp tau burden for a given level of EC tau (Figure 3).A significant interaction between APOE-ε4 and TREM2 (β=0.0186,p=0.0168) indicated that those with a TREM2 risk variant and 1 or 2 APOE-ε4 alleles had significantly more MetaTemp tau.Visualising the marginal effects highlights these results showing that APOE-ε4 homozygotes and TREM2 risk variant carriers have greater MetaTemp tau, and these differences increase with EC tau burden, independent of Aβ main and interactive effects with EC tau (Figure 3).We did not observe any significant effects of sex on MetaTemp tau (sex(F) (β= 0.0613, p= 0.1407); sex(F)*EC tau (β= -0.0504, p= 0.1496)) (Supplementary Table 7).
Where possible due to available data, we observed highly similar results in the HABS-HD sample.We observed significant effects of APOE-ε4 homozygosity on MetaTemp tau both as a main effect (β=-0.216 p=0.0069) and interacting with EC tau burden (β=0.156,P=0.0047) (Figure 3).This replicates the association we observed showing that APOE-ε4 homozygotes have greater MetaTemp tau, and these differences increase with EC tau burden independent of Aβ effects.Similar to the discovery sample, we did not observe any significant effects of sex on MetaTemp tau (sex(F) (β= -0.013, p= 0.74); sex(F)*EC-tau (β= 0.0305, p= 0.31)) (Supplementary Table 8).Like the previous analysis for EC tau, our results are likely not confounded by race in the replication sample.When self-reported race was included as a main effect and interaction term with genetic variables in our model, these added variables did not have significant influences on MetaTemp tau (Supplementary Table 9).

Variable genetic effects at different stages in the canonical amyloid cascade pathway.
Finally, we investigated the variability in the direct, mediation, and total effects of upstream pathology on downstream tau pathology for different genetic profiles.This allows us to probe each aspect of the AD cascade and estimate which groups are likely to have higher downstream pathology for a given level of upstream pathology (i.e. if a population has greater EC tau for a given level of Aβ and how this may result in higher levels of MetaTemp tau).To do this, in each group we calculate the direct effect of Aβ on EC tau (DEAβ ->EC tau); the direct effect of EC tau on MetaTemp tau (DEEC tau ->MetaTemp tau); the direct effect of Aβ on MetaTemp tau (DEAβ - >MetaTemp tau); the mediation effect of Aβ through EC tau on MetaTemp tau (MEAβ ->EC-tau -> MetaTemp tau); and finally the total effect of Aβ on MetaTemp tau (TEAβ -> MetaTemp tau).We observed significant effects in all AD pathways except the DEAβ ->MetaTemp tau regardless of genetic profile due to MEAβ ->EC-tau -> MetaTemp tau being consistently significant.That is, in these data the role of Aβ on MetaTemp tau is via the canonical pathway acting through increases in EC-tau.When we contrast these effects amongst the different genetic groups, we observe differences in the total effects of Aβ on MetaTemp between APOE-ε4 homozygotes, where this population has significantly greater levels of MetaTemp tau for a given level of Aβ TEAβ -> MetaTemp tau: APOE-ε4 (2-alleles) vs (0-alleles)=0.003,p=0.022;(2-alleles) vs (1-allele)=0.0029,p=0.0335)).This is due to differences in both DEAβ ->EC tau and DEEC tau ->MetaTemp tau for APOE-ε4 homozygotes (Supplementary Table 10).This implies that for APOE-ε4 homozygotes, a given level of Aβ leads to higher EC-tau, and a given level of EC-tau leads to higher MetaTemp tau.As such, this population sees greater levels of MetaTemp tau for a given level of Aβ due to increased effects of Aβ on EC tau aggregation and EC tau spread into the neocortex.There were no significant differences in the TEAβ -> MetaTemp tau across other genetic groups, although of note was a non-significant numerical difference in the TEAβ -> MetaTemp tau for females vs males (females vs males=0.0005,p=0.1), which was driven by significant differences in the DEAβ - >MetaTemp tau (females vs males=0.0008,p=0.036).This implies that for a given level of Aβ women have greater levels of EC tau, although, this doesn't require that females have reliably greater MetaTemp tau for the same level of Aβ.Relative effects and interpretations were similar in the replication sample (Supplementary Table 11).

Discussion:
Here we used causal path analyses structured on the canonical AD pathological cascade where Ab is the initiating event, followed by increased tau burden in the EC, followed by tau involvement of neocortex.Using this path framework, we examined how genetic variation relates to the burden of tau pathology in the medial temporal and neocortex.We provide compelling evidence for heterogeneity in how regionally specific tau pathology is distributed based on different genetic traits, thus providing insight into the biological mechanisms that may govern increased tau pathology.Furthermore, we provide empirical evidence that may explain variable gene and sex related treatment effects of recent anti-amyloid immunotherapy trials.
Using rare polymorphisms on the coding region of the TREM2 gene, we find that trait differences in the function of TREM2 plays a role in the spread of tau from the EC into the neocortex.We observed a strong effect showing that for a given level of tau in the EC, individuals with a gene burden of TREM2 have greater levels of neocortical tau after accounting for other upstream and confounding variables (i.e.sex, APOE-ε4, age, Ab).The function of TREM2 has been linked to tau spread through several putative mechanisms 18,19 .In particular, animal models have highlighted that TREM2 risk variants result in hypoactive TREM2 which may disrupt microglial inflammatory signalling to tau and may promote tau transmission through aberrant microglial activity 23,35-38 .Prior neuroimaging studies in humans has similarly implicated microglial activity in tau deposition in the neocortex 39 .Furthermore, CSF soluble TREM2 (sTREM2) levels are predictive of the transition from pre-clinical to clinical AD and are associated with CSF tau levels 18 .Alternate accounts have also shown that increased CSF levels of sTREM2 may be protective against tau and Ab accumulation 40 .Our work adds to this body of literature by interrogating the function of TREM2 as a parent trait variable rather than an indicator which varies as a function of pathological state, providing invivo evidence into how dysfunction in TREM2 enters the AD cascade, working to exacerbate tau spread from the EC into the neocortex likely through aberrant microglial function.
We observe strong effects of APOE-ε4 homozygosity on both tau in EC and neocortex.Specifically, across levels of Ab APOE-ε4 homozygotes had substantially more EC-tau.
Further, for a given level of EC-tau APOE-ε4 homozygotes had greater levels of neocortical tau.Critically, this relationship between APOE-ε4 homozygosity and variable neocortical tau burden was observed after accounting for the levels of upstream Ab, and the interaction between high Ab and EC tau.The net result of these effects means that for a given level of Ab, APOE-ε4 homozygotes have a greater level of neocortical tau than non-carriers and heterozygotes.Multiple lines of evidence have shown that overexpression of APOE4 increases tau phosphorylation 16,41 and spread of tau 11,14 .Prior evidence from APOE-ε4 models shows that the activity of neuronal 42,43 , astrocytic 44 and microglial 45,46 cells increases tau pathology.Furthermore, APOE-ε4 knock in mice have displayed hyperexcitability in medial temporal regions 43,47 , a potential driver of tau accumulation 48 .Converging human neuroimaging studies have implicated the APOE-ε4 allele with increased levels of medial temporal tau independent of Ab [49][50][51][52] .Our work builds on these previous accounts showing that APOE4 also plays a role in tau deposition outside of the EC and through tau mediated routes.Of note, these previous studies generally grouped APOE-ε4 carriership as a binary variable and did not contrast homozygotes with heterozygotes.We observe that it is homozygotes that are more susceptible to increased levels of tau after accounting for Ab.Given the substantially greater risk of having clinical AD 8 and Ab positivity 9 in homozygotes compared to heterozygotes, this supports recent work showing that statistical aggregation of APOE-ε4 homozygotes and heterozygotes in one group may not be appropriate 9 .Although we were well powered to make comparisons between APOE-ε4 homozygotes and heterozygotes, further work in larger samples will be required to fully understand the differences in tau accumulation between these groups.Recent imaging studies have suggested that APOE-ε4 potentiates the relationship between Ab and tau pathologies 53,54 ; our results provide some support of this model, highlighting that Ab and APOE-ε4 interact to increase EC tau pathology.However, we suggest a refinement to this model whereby APOE-ε4 also potentiates the relationship between tau burden in the EC and spread into the neocortex independent of Ab.
We have shown that APOE-ε4 homozygotes have increased primary tau pathology in the EC at lower levels of Ab, and increased neocortical tau pathology at lower levels of EC tau.This strongly suggests that homozygotes should be treated earlier with anti-amyloid treatment (i.e. at lower levels of Ab) to reduce tau, not simply because they begin depositing Ab earlier than other genotypes 55 but because this Ab drives higher tau.In addition, the effects of homozygosity on increased neocortical tau relative to EC tau raise questions about the need for anti-tau therapy in this group.This empirical evidence may provide some of the biological underpinnings explaining lack of treatment effect in APOE-ε4 homozygotes in both the Lecanemab and Donenamab trials 1 2 .
In addition to the independent effects of TREM2 and APOE-ε4, we observed a significant interaction between these two genetic risk traits.Individuals with a TREM2 risk variant and an APOE-ε4 allele had higher levels of neocortical tau for a given level of EC tau, implicating interactive factors between APOE4 and TREM2 on tau aggregation.APOE is a ligand of TREM2, with models of TREM2 variants (R47H, R62H, D87N) showing a decreased binding affinity between TREM2 and APOE in vitro 19,[56][57][58] .Furthermore, prior work shows that APOE4 isoforms are recognised and engulfed by TREM2 at different rates than other APOE isoforms 59 ; this differential binding of TREM2 to APOE4 may result in an impaired switch of homeostatic microglia to disease associated microglia in AD 18,20,21 .Previous neuroimaging studies have also implicated the APOE-ε4 allele as a modulating factor between microglial activity and tau spread independent of Ab 49 .Our results support this previous human work highlighting that genetic traits that may manifest in aberrant interactions between TREM2 and APOE4 likely have a profound effect on the spreading of tau from the EC into the neocortex.
After accounting for upstream pathologies, we observed that females who harbor a risk variant in TREM2 have higher levels of EC tau after accounting for all other upstream or confounding variables (i.e.Ab, APOE-ε4 and age).Previous work has pointed to interactive factors of microglial activity and sex, implicating a greater role of microglia in tauopathy for females 60 .
Here we show similar trait interactions between the risk gene burden of TREM2 and female sex in EC tau after accounting for upstream variables.In addition, when investigating how sex interacts with Ab we observe that females have higher levels of EC tau for a given level of Ab than their male counterparts.This result fits well with previous accounts showing females have higher levels of medial temporal lobe tau after controlling for Ab [31][32][33] .We did not observe significant effects of sex on tau in neocortical regions suggesting that females are more susceptible to early tau deposition in the EC but may not show differences in tau spreading into the neocortex.This is further reflected in the small differences between females and males in the total effect of Ab on MetaTemp tau, which is predominantly driven by a larger direct effect of Ab on EC-tau in females.This suggests that females should see similar benefits in antiamyloid treatment as males but may require treatment at lower levels of Ab --so as to be at similar levels of primary tau--or to be screened for both Ab and tau, ensuring that females do not have more advanced tau pathology than their male counterparts.These findings may also provide some insights into the discrepancies between the Lecanemab and Donenanab trials, whereby females did not see the same benefit as males in Lecanemab but did in Donenanab 1 2 .It is feasible that the multimodal screening for intermediate tau and Ab positivity in Donenanab vs. unimodal screening of Ab positivity in Lecanemab ensured that the sex related differences in early tau burden were ameliorated.Confidence in such an interpretation will require further exploration however.
Our interpretation and approach have several limitations.First, we note that our interpretation of our results in light of the recent anti-amyloid trials is highly susceptible to confirmation bias.
Although we initiated this work prior to the release of the results of these trials, we did undertake much of the preparation of this manuscript knowing that APOE-ε4 homozygotes and females may have variable treatment outcomes.Although our results fit well in existing literature, further work is required to understand the reasons that these populations saw attenuated or no benefit in the respective trials.Second, although our model is grounded in generally well accepted neuropathological staging of AD 61,62 , it is cross sectional so further modelling work on longitudinal multimodal imaging datasets is required to fully elucidate the dynamics of AD pathophysiological changes.Third, our analytical decision to consolidate multiple TREM2 risk variants into a risk variant carrier status assumes a similar biological role of each risk variant and does not apply a weighting to individual SNPs 63 .Furthermore, the 6 SNPs were not fully sampled in each cohort with 4 of 6 sampled in ADNI and some variants were imputed from the WGS in A4.Therefore, it is possible that some individuals who have a TREM2 risk variant were assigned to the non-carrier group due to lack of available data.
However, both of these analytical decisions would work to push our results closer to the null (i.e. more prone to type II error) and thus do not negate the findings presented here.Future work on larger and more complete datasets will afford a more granular appraisal of the biological role of each risk SNP on the AD cascade.Similarly, although we validated our findings related to sex and APOE-ε4 in an ancestrally diverse sample, we were unable to undertake robust ancestral stratification to fully understand potential ancestral differences that are observed in AD genetic risk 8 .However, we do note that there was a reasonable representation of each ethnicity in our validation sample of APOE-ε4 homozygotes.Further, although our sample is large, the number of APOE-ε4 homozygotes is still small.However, we did replicate our findings in two independent and relatively heterogeneous samples, giving further confidence to our findings regarding APOE-ε4.Finally, due to the incomplete sampling of TREM2 SNPs in HABS-HD, we were unable to run a replication analysis and as such further work will be required to validate our TREM2 findings.

Conclusion:
Our genetic architecture at birth governs the function of our biological systems throughout development, ageing, and neurodegeneration.Here we have used genetic variation to provide a deeper understanding of the biological mechanisms that drive AD pathophysiology.We show in a diverse sample of over 1300 participants that females and APOE-ε4 homozygotes are more susceptible to the primary accumulation of tau, with greater EC tau for a given level of Ab.Furthermore, we observed for individuals with risk variants in TREM2 and APOE-ε4 homozygotes there was a greater spread of primary tau from the EC into the neocortex.These findings offer insights into the function of sex, APOE and microglia (vis a vis TREM2) in AD progression and have implications for determining personalised treatment with drugs targeting Ab and tau.

Figure Captions
Figure 1 Canonical AD cascade.The top panel shows the directed acyclic graph used to model the potential pathways between genetic variables and pathology.Each arrow represents a potential pathway from a genetic variant (grey node) through an upstream pathology (i.e.Aβ or EC tau) that varies levels of downstream pathology (yellow node).The bottom panel indicates the stages and spatial distribution of AD pathology throughout the cascade.We modelled the initial seeding of tau using the EC region of interest.Early neocortical tau was modelled using the meta temporal region of interest.

Supplementary Files
This is a list of supplementary les associated with this preprint.Click to download.giorgio2024tables.docxgiorgio2024supplementarymaterial.docxgiorgio2024supplementarymaterial.docx

Figure 2
Figure 2 Genetic influences on Entorhinal Cortex (EC) tau.Lines show the estimated marginal levels of tau pathology for individuals with varying genetic profiles at different levels of Aβ.Bar graph shows estimated levels of tau pathology based on sex and TREM2 risk variant carrier status.Different effects in the discovery sample for a. APOE-ε4, b. sex, c. interaction of sex and TREM2 risk variant carrier status.Different effects in the replication sample for d.APOE-ε4 and e. sex.f.Causal path model to estimate EC tau.Values in parentheses indicate presence of risk polymorphism or number of risk alleles.The path model shows the causal path modelled whereby levels of EC tau are predicted by genetic variant, Aβ centiloid (CL) and their interactions.

Figure 3
Figure 3 Genetic influences on MetaTemp tau.Lines show the estimated marginal levels of MetaTemp tau pathology for individuals with varying genetic profiles at different levels of EC tau.Different effects in the discovery sample for a. APOE-ε4, b.TREM2, and c. their interaction.Different effects in the replication sample for d.APOE-ε4.e. causal path modelled whereby levels of MetaTemp tau are predicted by genetic variant, Aβ centiloid, EC tau and their interactions.

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